JPS5965036A - Arachidonic acid analog, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel tetrazole salts of unsaturated fatty acids;
It relates to their use in the prevention and treatment of inflammatory processes, pain and allergic reactions, and to pharmaceutical compositions containing these compounds and methods for their production.

Arachidonic acid, prostaglandin and leuco)!
It exhibits selective inhibitory activity against inflammatory agents such as J-cn (1 sucotrisn) and thromboxane, a platelet coagulation agent, or enzymes involved in the synthetic pathway of thromboxane. These compounds are useful in the modulation of inflammation and pain, such as in the prevention or treatment of rheumatoid arthritis, in the modulation of allergic origins, such as in the prevention or treatment of bronchial spasm due to asthma, or in the inhibition of platelet aggregation.

The compound structurally closest to that of the present invention is Holland 11
% WANL -7,21'1. 2-descarboxy-2-(tetrazol-5) disclosed in No. 860 Q
-il) Prostaglandin; Peruvian Patent No. BE'
FR 2,264,5
Vitamin I compounds as disclosed in French Patent No. 22; long chain fatty acid amides as disclosed in French patent no. Patent No. Ngtke;
a, e o 4. It is an unsaturated fatty acid amide having 163 to 24 carbon atoms and disclosed in No. oss. Quaternary ammonium hydroxamate is disclosed in U.S. Pat. No. 3,427,
No. 316, N-substituted fats are also described as cholesterol-lowering agents.

/ , Mad, Chsq>Ha -l 2, 1
184 (1975) describes a congener of lysophosphatidylethanolamine that inhibits the activity of phosphonin. Eicosate line-5, 8, 11,
14-oic acid and its salts and esters are described in Peruvian Patent No. 711.448.

One aspect of the present invention is that formulas (1), (2) and (3)B
is c=c or c=c - D is C-(,', c=c or c=c, E is C-C
%C=C or C=C), FdC-C, C=C
51 is c=c and υ, Zii, CH,, CH, CH,,
CH, CH, CH,, CM, C'H2CH, CHl, and X is 1-H-tetrasyl-5-yl, C(0)NHOH%C(0)CM, OH or C0NIi
] The compounds represented by the following formula and their pharmaceutically acceptable non-toxic salts can be administered in therapeutically effective amounts to reduce inflammatory and allergic reactions in mammals. Concerning how to treat.

Yet another aspect of the present invention is a pharmaceutical composition comprising a suitable pharmaceutical excipient and a compound of formula (3) or a pharmaceutically acceptable non-toxic salt thereof. relating to things.

Finally, another aspect of the present invention is the following formula (11, (
The present invention relates to a method for producing the compounds of 2) and (3) and the corresponding JJa & scientifically acceptable non-toxic salts.

As used herein, "1-H-tetrazol-5-yl" means that the H atom is attached to the tetrazole ring at the l-position and the x-B-tetrazole ring is attached to the unsaturated aliphatic chain at the 5-position. means the group N4CH-. Position numbers of heterocycles shall follow IUPAC nomenclature.

"Rysylhydroxylamine" as used herein refers to the group -C(0)NHOII. Acyl hydroxylamines are also referred to as hydroxamic acids.

[Hydroxymethylketone] as used herein refers to the group -C(OCH,OR).

"Unsaturated fatty acids" as used below have 3 to 5 carbon atoms in the carbon chain.
Examples of fatty acids having multiple double or triple bonds are arachidonic acid, linoleic acid, eicosatrienoic acid, eicosatriinoic acid, and the like.

The carbon position numbers of fatty acids are according to the IUPAC nomenclature as follows: (Z) is used in a conventional manner to indicate the cis stereochemistry of the triple bond, and is used to indicate the carbon atom where the double bond is present. Rank lol
Follow the t-number.

To name compounds containing triple and double bonds, the classical nomenclature of -ynyl and -enyl, respectively, is used.

"Pharmaceutically acceptable non-toxic salts" refers to salts derived from pharmaceutically acceptable non-toxic inorganic and organic threads.

Examples of nomenclature are provided in the next section of this specification.

One group of preferred compounds of the invention are compounds of formula (1):
NHOH, C(0)CM, On or coin stage available, -
4ft-'l is cll, C1l, CH.

or CH, CE, CM, CE,] Representative compounds of this group are: 5-(A"?-7(Z
), l 3 (Z)-dixn-4.10-cyynyl)-
1-H-tetrazole; heneicosa-8 (21,14
(Z)-Diene-5,11-cyinoylhydroxylamine; l-hydroxydocosa-9 (Z), ts (Z)
-diene-6,12-diyn-2-one heneicosa-8(2), 1.4 (Zl-diene-5-11-
Docosa-8(Z), 14(Z)-Diene-5゜11-Duinyomido8 5-(heneikosa-7(Z), 13(Z)-Diene-
4,10-cyynyl)-1-4-tetrazole; docosa-8(Z),14(Zj-diene-5°11-cyinoylhydroxylamine; 1-humano*cy)! J Kot-9 (Z), '15 (Z)-Jen-6.12-
Diyn-2-ones □Another group of preferred compounds of the invention are compounds of the following formula (1): [wherein X is 1-H-tetrazol-5-yl, C(OI
NHOH%C<0) CD, OM or FiCONH, and UZId, CM, CM.

CMs or CM, CH, CM, CB].

Representative compounds of this group are the following formulas =s-
(Z Iko? -7 (Z), 10 (Z), 13 (Z) -
) Tzen-4-ynyl) -1-H-tetrazole; -5-ynoylhydroxylamine; ! -Hydroxydocosa-9 (Z), 12 (ZJ.

15(Z)-) Lien-6-in-2-on; y-work to 5-1 4:y? -7 (Z), 10 (Z).

13(Z)-)Tzen-4-ynyll-1-H-tetrazole; docosa-8tZ), 11(Z), 14(Z)-trien-5-ynoylhydroxylamine; heneicosa-8(Z), 11 (Z), 14 (Z)-triene-5
-ynamide; docosa-8(Z), 11(Z), 14(Z)-trien-5-ynamide; and l-hydroxytrieicosa-o(Z), 12(Z)
, 15(Z)-trien-6-yn-2-one.

Other suitable compounds are those of the formula (II); [wherein X is 14-tetrazol-5-yl, C(0)N
HOE, CC0) CH, OH or) CONII].

Representative compounds of this group are: 5-(nonafcar4 (Z), 7121, 10 (Z),
13°[1-tetraenyl)-1-H-tetrazole; eicosa-5 (Z), 8 (Z), 11 (Z).

14(Z)-tetraenoylhydroxylamine; 1-
Hydroxyheneicosa-6 (Z), 9 (Z)
, 12(Z), 15(Z)-te)raey-2-t; and eicosa-5(Z), 8(Z), 11(Z).

14(Z)-Tetraene compound.

The most preferred compounds of the invention are those of the following formula: where X is 1-H-tetrazol-5-yl, CCUI
NHOH,C(0)CH,OH or C0NE]
.

The representative compound 'b+ of this group is the following filling =5-(
nonadeca-4,7-111,13-tetrainyl) -
1-E-tetrazole; Eicosa-5,8,11,14-tetrainoylhydroxylamine; 11,14-tetrine compound.

The most preferred compounds of the invention are those of formula (1): where X is 1-H-tetrazol-5-yl, C(OI
NHOM, C'(O)CE, OH or C0NH].

Representative compounds of this group are as follows: 5-(eicosa-4,7,10,13-tetrainyl l -1-
II-tetrazole; heneicosa-5,8,11,14-tetrainoylhydroxylamine; l-hydroxydocosa-6,9,12,15-tetrain-2-one; and heneicosa-518,11,14-tetrine-2-one Mid.

Methods for fabricating fatty acid precursors with various combinations of double and triple bonds are known.

Eicosa-5 (Z) and 8 (Z) having 20 carbon atoms.

Separation of 11(2'1.14(Z)-tetraenoic acid (arachidonic acid) from BeIη, J. Biol, Cham, incorporated herein by reference.

0,455 (1928).

'Carbon number 19 (t') nona f car 5 (Z), 8 (Z
).

11(Zl, 14(Z)-tetraenoic acid and carbon number 21
Heneicosa-5 (Zl, 8 (Z).

11 (Z), 14 (Z) -f? xn9 (D
Synthesis C, RECU cited herein as a reference
- Described in EIL, Danyu, 461 (1968).

Oftateker 8 (Z), 11 (Z), 14
(Z)-trienoic acid, nonadeca-8(Z), '11
(Z), 14(Z)-) lienoic acid, heneicosa-8 (
Z), 111Z), 14(i)-trienoic acid, and dococer-8(Z), 11(Z), 14(Z)-trienoic acid are described by RECU, which is cited herein by reference.
EIL, 87.461 (1968).

Synthesis of octadeca-9,12,15-trienoic acid (linoleic acid) is incorporated herein by reference.
Cham, Soc., 4049 (1956).

The preparation of eicosa-5,8,11,14-tetreinoic acid is described in J.
, Chum, Soc, 2771 (1969).

14.15-dehydroarachidonic acid (eicosa-5 (Z
), 8(Z), 11tZ)-) diene-14-inoic acid) and its preparation #c, J, Am, cited herein by reference.

ch",Coc,・1°4・"750 (19B2)
.

SatsujogatL-C.
15.6-. 8.9-. 11.12-dehydroarachidonic acid and its synthesis in J. Am, Chgm, Sac, cited herein by reference.

104.1952 (1982) and 7gtrahs-d
ron Lstt, 23% 1651 (1982)
It is described in

Eif v-4(Z), 8(Z), 11-(Z
).

14 (Zl-tetrae/acid;
Z).

14(Z)-tetraenoic acid; x icocer 8 (Z), 11 (Z), 1
4 (Z'1.

18(Z)-tetraenoic acid; octadeca-5(Zl, 8(Zl, 11(Z)
).

14(Z)-tetraenoic acid; )"=+-vs(Z), 8(Z), 11(zl,
14 (Zl-tetraenoic acid; nonadeca-4(Z), 7(Z), 10CZ).

1 B (Z)-tetraenoic acid; eicosa-4,8,11,14-tetreinoic acid; and octadeca-5,8,11,14-tetreinoic acid, and the manufacture thereof is incorporated herein by reference. It is described in RFCUEIL, 1943 (1971), which is cited as a document.

Ko (ko e-8 (Z), 11 (Z), 14
(Z)-trienoic acid, octadeca-6(Z), 9
(Zl, 12(Zl-) lienoic acid, nonadeca-a(Z)
.

1t(Z), 14(Z)-) Lien-5-inoic compounds and their preparation are described in RECUEIL, 94262 (1975), which is incorporated herein by reference.
It is described in

Nonadecatrienoic acid, octadecatrienoic acid and other substituted trienoic acids are described in t<p, cttEf L, 94.269 (1975), which is incorporated herein by reference.
And no? It is described in ECUEIL, 87.461 (196B).

The synthesis of arachidonic acid and its related age-saturated compounds is described by RECUEI, which is incorporated herein by reference.
L, 82.1615 (196B).

The synthesis of naturally occurring polyunsaturated fatty acids is described in “progυrss 1nthe
Chamistry of Fats and
0th11IrL i p i d so, 9(2),
119-1″57 (1966), Pargamon p
ress, Oxford, publ.

It is described in

The synthesis of unsaturated fatty acids not specifically described in the above-mentioned documents is carried out according to the methods described above, starting from suitable different fatty acid precursors.

Formulas (1), (2) and (3) where B and F are C=C, A and D are C=C, E is C-〇, and X is C0OH
In the compound, B and F are C-=C, A and D are C=C,
E is c-c and X is 1-II-tetrazol-5-
An intermediate in the synthesis of compounds of formulas (1), (2) and (3), wherein 5-hexynoyl, C(0)NIIoll, C<0ICE, OH and CONM, A bis(halomagnesium) salt, preferably a habis(bromagnesium) salt, of a compound or a 4-pentylene compound is reacted with a l-halo, preferably a l-bromo-2,8-dinine-5-dione. Manufactured by This reaction is 0~
1 to 7211 at a temperature of 65°C, preferably 65°C
The process is preferably carried out for about 25 hours in an ethereal solvent, preferably tetrahydrofuran. Each mole of 2,8-diene-5-yne is ~3
, preferably 2 mol of acetylenic acid are used.

The reaction is the halogenation or cyanide of the catalyst t, i1F, 1
It is carried out in the presence of copper, preferably all copper chloride. l-Haloalka-2,8-diene-5- used in the reaction
In addition, the reaction with a halogenating agent such as triphenylphosphine/carbon tetrachloride, phosphorus trihalide, or triphenylphosphine/cyonogen bromide, preferably the latter from the corresponding l-hydroxyalka-2,8
-Made from diene-5-yne. The reaction is carried out in an inert organic solvent, preferably methylene chloride, at 0-50°C.
, preferably at about 25° C., for 1 to 24 hours, preferably about 4 hours. The halogenating agent and alcohol are present in equimolar amounts. l-hydroxyalka-2,8
-Dien-5-yne is prepared in a water-miscible organic solvent such as tetrahydrofuran, ethanol or methanol, preferably methanol, optionally in the presence of 1 to 40%, preferably 5% by volume of water, with an acid such as acetic acid. , sulfuric acid or p-toluenesulfonic acid, preferably ap-toluenesulfonic acid, from the corresponding 1-(tetrahydrobyranyloxy)-alka-2,8-tzen-5-ynes. The reaction is carried out at 0-50°C, preferably about 25°C, for 1-12 hours, preferably 2 hours. 1-(tetrahydropyranyloxy)alka-2,8-
dien-5-yne, 1-()riphenylphosphonio)
-Alk-6-en-3-ynhalide, Coffee K11l
ltlγγgo vomits” Punishment animal I Yogo white Kokokoko 4=’l
'll'N*'1ll1 example + 1-()liphenylphosphonio)-dode-6-ene-6-isopromide (
1# manufacturing method is J, Atn, Chsm, Sea, 104.
1753 (1982)) and 2-(tetrahydropyraniloxy)-acetaldehyde (# notation is Ch s m.

pharm, Bull,, 11,188 (196
3)) is produced by the Wittig reaction between 3) and 3). The ylide can be used in a solvent containing from 0 to 25%, preferably 10% by volume, of hexamethylphosphoric triamide, such as dimethyl sulfoxide or tetrahydrofuran, 4
l-4L< in tetrahydrofuran, -100
phosphonium halide and equimolar amounts of a strong base, such as sodium hydride, phenyllithium or butyllithium, preferably butyllithium, at -25°C, preferably -78°C for -6 hours, preferably 1 hour. It is produced by a reaction. 2-(Tetrahydrobyranyloxy)acetaldehyde and hyphosphonium base are used in fathomolar amounts.

1-(tetrahydrofuranyloxy)-alka-2,8-
Dien-5-yne is a 1-haloalk-2-ene, e.g.
m, Soc, 3868 (described in 19571 °C) and l-(tetrahydropyranyloxy)hexo-2
It can also be produced by a coupling reaction between -en-5-yne. The coupling reaction is carried out in an aqueous or hydroalcoholic solution, optionally in the presence of an IEI copper salt, such as copper chloride, at a temperature of 0 to about 100 DEG C. for a period of 1 to 24 hours. i-4tetrahydrobyranyloxy)hexo-2-
En-5-ynha, dihydropyran and hyexo-2-en-5-yn-1-ol (manufactured by Bull, Sac
, Chptn, Frat*ca.

2105 (described in 19631) produced by a catalytic reaction. If this reaction is carried out without a solvent or in the presence of a specific solvent such as needle or methylene chloride, the compounds in which the acid is eg sulfuric acid, hydrochloric acid or the like are prepared according to Reaction Scheme 1.

Reaction formula l ↓ (1) R-CONHt ↓ (■) R-CN ↓ In the above formula, R-COOH is A is c=c or c=c;

B is c=c or c=c; D is c-c, c=c or C=C; E is c-c, c
=c or C=C; F is c-c%c=c or c=c
and X is C0OH, and is an unsaturated fatty acid of formula (11, +23 or (3)).

In the following description, Roman numerals in parentheses indicate steps in the above reaction formula.

The preparation of tetrazole derivatives of unsaturated fatty acids having a carbon chain of 18 to 22 is carried out by adding a suitable unsaturated compound of formula 111, (2) or (3), where X is coon, in a neutral organic solvent, preferably dichloromethane. Fatty acids, such as arachidonic acid and carbonylsoimidazole, in a molar ratio of 1 to 7
This is preferred because the reaction time is preferably 4 hours. The product of this reaction is then reacted with a large excess of ammonium hydroxide for 24 to 64 hours, preferably 48 hours. Technically speaking, any other unsaturated monofatty acid compound (depending on the unsaturated fatty acid used initially) can be obtained.

A solution of compound (1) in a basic organic solvent, preferably pyridine, 't<-'-organosulfonyl halide, preferably <I>
ri, p-toluenesulfonyl chlorite tramol ratio l:
Add at l. This mixture is allowed to react for 12 to 48 hours, preferably 24 hours, and the reaction solution is poured into water. From the aqueous phase, eicosa-5(Z), 8(Z), 11(Z),
14 (Z)-fto5:X-7nit IJ A/(m
1 or any other fatty acid 2) is extracted.

The extract is then purified by methods known in the art.

Compound 1m (1) is then treated in a neutral polar solvent, preferably trimethylformamide, optionally in the presence of a Lewis acid, such as boron trifluoride, in an excess amount, preferably 3 mol, of an alkali metal azide, preferably sodium azide and an excess amount, preferably 3 mol, of ammonium halide, preferably ammonium chloride, from 80 to 120°C,
The reaction is preferably carried out at a temperature of 100 DEG C. for 16 to 48 hours, preferably 2'4 hours. In this reaction, other azide ion sources, such as aluminum oxide and hydry n-
Butyltin azide may also be used.

Then the product 5-(nonadeca-4(Z),?(Z),1
0(Z), 13(Z)-tetraenyl)-1LH-tetrazo-pv (W) is separated by a known method.

Other tetrazole derivatives of unsaturated monovalent fatty acids have X as C0
It is produced by method -1- using one of the unsaturated fatty acids of formulas (11, (2) and (3) of OH) as a starting material.

In addition, the production of unsaturated fatty acid amides ¥a4 is possible by first converting the acid into its activated derivatives, such as acyl hafride, acid anhydride, mixed acid anhydride, alkyl ester, substituted or unsubstituted phenyl ester, thioalkyl ester. , thiophenyl ester, and cylimidazole. The activated conductor is then reacted with ammonia or aqueous ammonia in the presence or absence of a suitable water-miscible or immiscible organic solvent, such as methanol, ethanol, cyclomethane, etc., to produce the hydramide.

The reaction is carried out for 1 to 96 hours at -30 DEG C. to the boiling point of the solvent or solvent mixture used. In addition, Ryo Mido is
By heating unsaturated fatty acids and amides together,
Alternatively, it can also be produced by heating ammonium salts of unsaturated fatty acids. This reaction is carried out in the absence of a yeast or in the presence of a solvent, such as toluene.
It is carried out for 1 to 12 hours at a temperature of 0°C. In addition, amides include nitriles of unsaturated fatty acids, inorganic or organic acids or bases,
For example, it can also be produced by hydrolysis using hydrochloric acid, sulfuric acid, or p-toluenesultetrabutylammonium hydroxide. The reaction is carried out in water optionally containing a co-solvent such as methanol, acetic acid or diglyme at 1-95%, at a temperature of 1-95% from 0°C to the boiling point of the solvent used.
It will be held for 6 hours. Such methods are well known in the art and are described, for example, in "5ynthetic Organ
cChsmistry”, John Willry &amp;
5oz.

pxbl, Nsw York, 565-590
Page (19531 and “Compendium of O
rganic 5ynthstic Methods
w, Hunger Volume 1, Filmg-1ntgrscisnc
S., Nsw York, 203-230 (1971).

Tetrazole derivatives of unsaturated fatty acids are also patented in Germany.
It can be produced by the reaction between iminoethers of unsaturated fatty acids, RC(=NH)0-alkyl (eg, alkyl is C3 to C6) derivatives, and hydrazoic acids, as described in No. S, Ztsyo. Iminoether derivatives are nitrile derivatives of unsaturated fatty acids combined with alkanols (C1-C,) and strong acids such as hydrochloric acid or p-
) Obtained by treatment with luenesulfone.

The reaction between the iminoether and the hydrazoic acid is carried out in the presence of a solvent such as chloroform or dimethylformamide at 0-120°C for 1-72 hours. Tetrazole derivatives are, for example, “511nthatic”.
Organic Chemistry”.

John Wilsy & 5ontt, publ',
, New York, p. 635 (1953), by the reaction between nitrite derivatives of unsaturated fatty acids and nitrous acid, as described in Annalss.

263.96 (1981) and 91 (1897)
)). The reaction is carried out in water or a mixture of water and a suitable organic solvent such as methanol or dioxane from 0 to 10
It is carried out for 1 to 24 hours at 0°C.

Compounds in which X is C(0)CE,OH are prepared according to the method of Scheme 2 from the appropriate unsaturated fatty acids described above.

Reaction formula 2 () () % formula % In the above formula, R-COOH is: A is C=C or C=C and t B is C=C or C=C; D or C-6%C= C or C-=C; E is c-6%
C=C or C=C; Nori or C"-C", C=
C or C═C; and X is C0OH, an unsaturated fatty acid of formula (1), (2) or (3).

The production of hydroxymethylketone derivatives (■) of various unsaturated fatty acids having 18 to 22 carbon atoms involves the treatment of unsaturated fatty acids such as arachidonic acid with trace amounts of tertiary organic compounds, preferably dimethylform. It begins by dissolving the compound in an inert organic solvent, preferably benzene, and reacting it with thionyl or phosphoryl norlide or phosphorous pentahalide, preferably thionyl chloride. 0 mixture
React for 8-32 hours, preferably 16 hours at ~25°C and then evaporate to dryness. The residual acid chloride (Vll
is dissolved in an inert organic solvent, preferably ethyl ether. This solution is cooled to -5-5°C, preferably 0°C, and a solution of azomethane in ether, preferably diethyl ether, is filtered to 51°C. Add in the amount of Il. 1 of this mixture
ether, which is allowed to react for ~5 hours, preferably 2 hours, and then converted to evaporation to make the residual diazoketone 01 miscible with water;
Preferably dissolved in tetrahydrofuran. To this solution is added an aqueous solution of a strong acid, preferably trifluoroacetic acid fL. The mixture is reacted for 2 to 8 hours, preferably 4 hours, and the target compound (■) is separated and purified by known means.

Hydroxymethylketone derivatives of unsaturated I fatty acids are /
, Org, Chgm, 25.4617 (1979), silinolides derived from unsaturated fatty acids, acid anhydrides or mixed acid anhydrides, and acyloxy- or alkylthio-substituted silylated ketene acetals. It can also be produced by reacting. This reaction is carried out in the presence or absence of a suitable organic solvent such as toluene or sophenyl ether and in the presence or absence of a Lewis acid catalyst such as stannic chloride at 0 DEG to 150 DEG C. for 5 minutes to 8 hours.

The decarboxylation reaction is carried out in the presence of an aqueous mineral acid, e.g. hydrochloric acid, in a suitable solvent, e.g. dioxane, at lO
It lasts from minutes to 3 hours. The hydroxymethyl ketone conductor of unsaturated fatty acids can be prepared using an acid such as hydrochloric acid or a base such as potassium hydroxide, in which the alkyl is C1 to C6 and 7
It can also be obtained by hydrolyzing acyloxymethyl ketone (CRCOCH, 0CO-alkyl) or halomethyl ketone (RCOCH, -). This reaction is carried out in an aqueous or aqueous organic solvent such as methanol, ethanol, etc. at a temperature of 0 to 60°C for 1 to 24 hours.
Time is done.

Reaction formula 3 illustrates the production of an unsaturated fatty acid conductor in which X is CC0INHOH.

・ Reaction formula 3 % formula % In the above formula, 7(-C00B means that A is C=C or C=C; B is C,=C or C=C; D is c-c%(, '=c or C=C; E is (:'
-4. c=c or C=C; 'F is c-
c%c=c or C-=C'; and X is C0OH.

Acylhydroxylamine fatty conductors of unsaturated fatty acids (xl
) is produced in two ways. First, acid (IX),
As mentioned above, an acid chloride, preferably an acid chloride (X
b) or into a lower alkyl ester (Xα), preferably a methyl ester. This reaction is carried out by treatment with a solution of hydrogen chloride in a suitable lower alkanol, preferably methanol, or with a diazoalkane, preferably diazomethane, respectively. The hydroxylamine product (XI) is then reacted with excess hydroxylamine in a solvent, preferably aqueous methanol, at a pH of 7 to 10, preferably 9, for 1 to 6 hours, preferably 1 hour. Separate by means of

Acylhydroxylamines can also be prepared by reaction between hydroxylamine and activated derivatives of unsaturated fatty acids, such as alkyl esters, substituted or unsubstituted phenyl esters, thioalkyl esters, thiophenyl esters, acylimidazoles, and the like. The reaction is carried out in an aqueous or organic solvent such as methanol, acetonitrile or acetone at 0°C to the reflux temperature of the solvent for 1 hour.
It will last for ~48 hours. Other acylhydroxylamines are described by Chum, Rsv, 32.395 (1945).
For the acid-catalyzed transfer of primary nitro derivatives of unsaturated fatty acids (RHO,) as described in
It will be held for ~24 hours. Also unsaturated fat U5t11. For example, Chsm, R
It can also be prepared by oxidizing oxime derivatives of unsaturated aliphatic aldehydes (RCH=NOH) with hydrogen peroxide as described in J.D. nv., 33.225 (1943).

This reaction is carried out in a solvent such as methanol or dichloromethane at 0-35°C for 1-6 hours.

Separation and purification of the compounds and intermediates described herein may be carried out, if desired, by suitable separation or purification methods, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, or thin layer chromatography. This can be done by a combination of these methods. For an appropriate separation method, reference can be made to the examples described later. However, other equivalent separation methods may of course also be used.9, Equation +
The salts of compounds 11, (2'' or (3)) can be converted into each other by taking advantage of the different solubility of the salts or by treatment with a suitably pretreated ion exchange resin.

-H 4H person υ0 or building's 4H tomono derogation I or te 4H descending temple i
A salt of an acylhydroxylamine or tetrazole derivative of a compound of formula (11, (23) or (3)) is a salt of formula (11, (23) or (3)).
), (2) or (3) by treating the acylhydroxylamine or tetrazole compound of (2) or (3) with at least one molar equivalent of a pharmaceutically acceptable base.

Representative pharmaceutically acceptable bases are sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, metal alkoxides such as sodium methoxide, trimethylamine, lysine, caffeine, and the like.

The reaction is carried out in water alone or in a suitable organic solvent such as violet solvent in combination with an inert water-miscible organic solvent or methanol or ethanol at a temperature of 0 to about 100°C, preferably room temperature. It will be done. Flexible, inert, water-miscible organic solvents include methanol, ethanol or dioxane. The molar ratio of formula 111, +23 or (3) to the base used is selected to be the expected ratio for either salt.

Salts derived from inorganic bases are Na) IJum, potassium,
Lithium, ammonium, calcium, magnesium,
These include ferric, zinc, copper, manganous, aluminum, ferric, and manganous salts.

Particularly preferred are ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary salts.
amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2
-diethylaminoethanol, 2-diethylaminoethanol, tromethamine, socyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrapamine, choline, peteine, ethylenediamine, glucosamine, methylglucamine, theopromine, purine, piperazine, piperaine , N-ethylpiperidine, polyamine resin, and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, socyclohexylamine, choline, and caffeine.

The salt product can be separated by conventional methods. For example, the reaction mixture may be evaporated to dryness, or the residue may be purified by conventional methods.

The compounds of the invention are tetrazole, hydroxyl hydroxylamine, hydroxymethyl ketone and amide derivatives of unsaturated fatty acids. These compounds exhibit a range of biological activities and influence the enzymatic processes leading to the in vivo synthesis of certain metal compounds or agents such as glosstaglandin or leukotrienes or platelet coagulation promoters. The compounds of the present invention are substitutes for grosstaglandin or leukotrienes.
Shows selective inhibitory activity against enzymes contained in 1 gram in diameter.

That is, it is a selective inhibitor of td) J-oxygenase and cyclo-oxygenase.

Because of their biological activity, these compounds are of prophylactic and/or therapeutic use for the prevention or treatment of symptoms of bronchospasm in
or a drug that can be used therapeutically. This compound is also useful in reducing pain and inhibiting platelet clotting.

Administration of the active compounds in the VJ db biological compositions described below can be by any of the accepted administration methods for agents that affect inflammation, pain, allergy, or platelet coagulation. These methods include local administration, parenteral administration, and in particular systemic administration or local administration. The compositions are preferably prepared in a single, precise form in the form of solid, semi-solid or liquid dosage forms, such as tablets, herbal medicines, pills, capsules, powders, liquids, suspensions, etc., depending on the intended method of administration. It may be in unit dosage form suitable for administration in dosages. The composition will contain a conventional pharmaceutical carrier or excipient and an active compound of formula 11), (2) or (3) and/or a pharmaceutically acceptable salt thereof. Furthermore, it may contain other pharmaceutical agents, chemical reagents, carriers, auxiliaries, etc.

The amount of active compound administered will, of course, depend on the subject being treated, the severity of the disease, the manner of administration and the judgment of the physician.

However, effective dosages range from 0.001 to 5 ON97 days, preferably 0.001 to 5+7 days, preferably 0.001 to 97 days. For people with an average of 70 hours, this is 0.07~
aooq/day, preferably 0.7 to 700 μ/day.

The novel compounds of the present invention can be formulated with suitable pharmaceutical excipients known in the art to produce particularly effective anti-inflammatory, anti-allergic and pain-free compositions.
Generally, the effective amount of active ingredient is about 0.001 of the total formulated composition.
~10% W/W. The remainder of the formulation, ie, about 90 to about 99.999% W/WVi, is suitable excipients.

For solid compositions, common non-toxic solid carriers include, for example, the pharmaceuticals mannitol, lactose, starch, magnesium stearate, sodium saccharine, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. The active compounds as mentioned above can be formulated as suppositories, for example, by using polyalkylene glycols such as glopylene glycol as carriers. Pharmaceutically administrable liquid compositions can be made into solutions or suspensions by, for example, dissolving or dispersing the active compounds as described above in water, aqueous dextrose, glycerol, ethanol, or the like. Optionally, the pharmaceutical composition to be administered may contain small amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, etc., such as sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, etc. may contain.

The actual methods of manufacturing such dosage forms are known;
or will be obvious to those skilled in the art; see, e.g. “Rs.
mington's°pharmacgutica
LScisncs”, Mack publish
ng Co.

Easton, psnnsylvania, 15th edition, 1975. The compositions or formulations that may be administered will contain the active compound(s) in an amount effective to alleviate the symptoms of sensitivities in each case.

For oral administration, pharmaceutically acceptable, non-toxic compositions include commonly used excipients such as pharmaceutical compounds mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose. , sucrose, magnesium carbonate, etc. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations, and the like. Such compositions may contain 10-95% active ingredient, preferably 25-70%.

Non-red injections generally feature subcutaneous, intramuscular or intravenous injections. Injectable compositions can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. I can do it. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, and the like.

Furthermore, according to the requirements, the pharmaceutical compositions that can be administered may contain small amounts of non-precious auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, etc., such as sodium acetate, sorbitan monolaurate, triethanol oleate, etc. It may also contain amines and the like.

A very recently devised method for parenteral administration is the use of controlled or extended release refills so that a constant dose of the drug is maintained. See, eg, U.S. Patent No. 3. '710,795 3 For systemic administration via suppositories, traditional binders and carriers include, for example, polyalkylene glycols or triglycerides; such suppositories preferably contain between 0.5 and 10% of the active ingredient. It can be prepared from a mixture containing in the range of 1-2%. .

For administration in an aerosol, the active ingredient is preferably applied in finely divided form together with surfactants and propellants. 0.01 to 20% by weight of the active ingredient
Preferably it is 0.04 to 1.0%.

The surfactant is, of course, non-toxic and preferably soluble in the propellant. , typical examples of such reagents include carbon atoms of 6 to 2
aliphatic polyhydric alcohols or their cyclic anhydrides, such as ethylene glyfur, Esters or partial esters of glycerol, erythritol, arabitol, mannitol, nlubitol, hexitol anhydride derived from sorbitol (sorbitan ester, commercially available under the trade name 1°5pans), and polyoxyethylene and polyoxyesters of these processes and esters. Propylene is the conductor. Mixed esters, such as mixed or natural glycerides, may also be used. Suitable surfactants are oleates or sorbitans, such as those with the trade names ZeArlαcIII C" (fluvitan sesquioate), @spαn so" ( Rubitan monooleate)
and 5pan85'' (sorbitan trioleate).The surfactant is
．． It may constitute 1-20% by weight, preferably 0.25-5%.

The remainder of the composition is conventional propellant. Liquefied propellants are typically gaseous under atmospheric conditions and condense under pressure. Some suitable liquefied propellants include those with a carbon number of 5, for example, the product name "F".
r56B". Mixtures of these can also be used.

When producing an aerosol, a container with a suitable pulp is filled with a suitable propellant containing the finely divided active ingredient and a surfactant. In this way the component gold is maintained under increased pressure, until it is released by the action of the pulp.

9. The following Preparations and Examples serve to illustrate and further elaborate the invention. They should not be seen as narrowing or limiting the invention in any way.

Example 1 Hekiy 2 (Zl-
To a solution of en-5-yn-1-ol (5y) was added 1, phosphorus oxychloride (0,1me) and 5 g of dihydrobilane. After 2 hours, the solution was diluted with saturated aqueous carbonic acid).
Added to um. The organic solution was dried and evaporated to give the title compound as an oil.

B, 1-(tetrahydrobyranyloxy)-tetrades-
Preparation of 2(Z), 8(Z)-dien-5-yne 1-tetrahydropyranyloxyhexo-2(Zl-en-5-yne (1,8 gl 1=2 aqueous ethanol 12
5-), and in this solution cuprous (0,2,9)
and 50% aqueous hydroxide sufficient to bring the pH to 9).
+7 um added. This mixture was heated to 60°C and p
1-bromooct-2 (Z
)-ene ('1.9 & ) was added over a period of 2 hours. After a further 3 hours the mixture was cooled, diluted with water and extracted with ether. The extra material was washed, dried and evaporated and the composition was chromatographed on silica gel and eluted with benzene/triethylamine (300/1) to give the title compound as an oil.

Example 2 A solution of 1-(tetrahydroxyvilanyloxy)-tetrazocar 2(Z), 8(21-dien-5-yne (1,1511) in methanol (30 m/) was prepared by adding p-toluenesulfonic acid monohydrate ) (30■) was added. The mixture was kept at 25° C. for 2 hours, then ether and water were added. The organic solution was washed, dried and evaporated to give the title compound as an oil.

Example 3 1-Hydroxytetrazocar 2 (Z), 8 (Z
)-dien-5-yne (61) Oway ) was dissolved in methylene chloride (10d), and triphenylphosphone (600w9) and cylinogenbromide 62
00■) was added. After 21 hours, the methylene chloride was removed under vacuum and the residue was dissolved in total hexane/ether (to/l;
υ/v)10I117! Extracted with.

The solution was filtered through silica gel (2y) and evaporated to give the title compound as an oil.

Example 4 To a solution of hexo-5-ynoic acid (448 μl) in tetrahydrofuran (10 fnI!l) was added a solution of ethereal ethylmagnesium bromide (3.0 molar solution 2
．． 7 td) was added. Mix #I4 was refluxed for 1 hour, then cuprous chloride (10η) and 1-promtetradeca-2(Zl, 8(Z)-dien-5-yne(
550 ■) was added. The reaction was refluxed for 24 hours, then cooled and dilute hydrochloric acid and ether were added. The organic layer was dried, evaporated and the residue was chromatographed on silica gel eluting with /v/υ) to give the title compound as an oil.

Example 5 Production of Sol Dichloromethane (70111/) Medium Eicosa-5 (Z
), g(Z), 1t(Zl, td Carbonyldiimidazole (
1,97Ji') was added. After 4 hours concentrated ammonium hydroxide (10-) was added and the mixture was stirred vigorously for 48 hours. The organic solution was separated, dried and evaporated to give the title compound as a solid, mp 35°C.

Eicosa-5 (Z), 8 (Z) in Pyridino (50m),
11 (Z), 14 (Z)-tetraenamide (2,
Add p-toluenesulfonyl chloride + to the solution of 4,9)
1.54#) was added. After 24 hours, the solution was poured into water9. The aqueous solution was extracted with ether and the extracts were washed with dilute hydrochloric acid, dried and evaporated to give the title compound as an oil.

Eicosa-5 (Z), 8 (Z), 11 TZ).

14(Z)-tetraenenitrile (1,4,9), sodium trichloride (1,061) and ammonium chloride (0
,85,! 9 ], dimethylformamide)' (8 ml
) for 23 hours at 100°C. This solution was added and diluted with ether (s o , p ). The ether solution was washed with water and then extracted with dilute potassium hydroxide. The aqueous extract was acidified with dilute hydrochloric acid and extracted with ether. The extract was dried and evaporated to give the title compound as an oil: nfrLr0.88 (triplet, 3H
, #-19);1. ao (multiple line, 6H, 77-16,
H-17 and H-181: 2.0 (multiplet, 4H, H-
12, H-ts); z23 (multiplet, 2H%H-3)
; 3.15 + triple line, 2H%H-21; about 2.8 (
multiplet, 6H, H-6, H-9, H-x2) and 5.3
~5.5 ppm (multiplet, sH, olefinic hydrogen). Mass spectrum m, /g = 328 (molecular ion)
.

Example 6 Similarly, following the methods A, B and C of Blowing Example 5, Eicosa-5(Z), 8(Zl, 11(Zl).

14 (instead of Zl-tetraenoic acid, the following starting material η: eicosa-5,8,11,14-tetrainoic acid; heneicosa-5(Z), 8(Z), , 11
(Zl, 14(Z)-tetraenoic acid; Heneicosa-5,8,11,14-tetrainoic acid; Nonadeca-5(Z), 8[Z), 11(21°14(Z)
)-tetraenoic acid; nonadeca-5,8,11,14-tetrainoic acid; docosa-51Z), 8(Z), 11(Z), 14(Z)
-tetraenoic acid; docosa-5,8,11,14-tetreinoic acid; eicosa-5,9,12,15-tetreinoic acid; docosa-6,9,12,15-tetreinoic acid; eicosa -4,7,10,13-tetra-1 neuic acid: dococer 4.7,10.11-tetrainoic acid; dococer-7,10,14,17-tetrainoic acid; heneicosa-8,11,14, 16-tetriinoic acid; eicosa-5,8,11-triinoic acid; nonadeca-8,11,14-triinoic acid; heneicosa-8(Z), 14(Z)-diene-5,1
1-Diinoic acid; Heneicosa-8 (Z), 11 (Z), 14 (Z)-
By using triene-5-ynoic azirad; 13-tetrainyl)-1-H-tetrazole; 5-(eicosa-4(Z'l, 7 (Z)
, 10 (Z), 1a(Z)-detraenyl)-1-
H-tetrazole; 5-(eicosa-4,7,10,13-tetrainyl
-1-11-tetrazole; 5-(71tadecar 4(Z), ?(Zl, t.

(Z'), 1a (Z)-ytraenyl l-1
-B-tetrazole; 5-(octadeca-4,7,10,13-tetrainyl) -1-H-tetrazole; 5-(heneicosa-4(Zl, '1(Z), 10(
Z), 13 (Z)-tetraenyl)-1-)l-
Tetrazole; 5-(heneicosa-4,7,10,13-tetrainyl)-1-11-tetosol, docosa-5°8.11
．． Via 14-tetrainamide, one point 106-108°
C; 5-(nonadeca-5,8,11,14-tetrainyl)
-1-#-tetrazole; 5-(heneicosa-5,8,11,14-tetrainyl)-1-H-tetrazole: 5-(nonadeca-3,6,9,12-tetrainyl>-
1-11-tetrazole; 5-(heneicosa-3,6,9,12-tetrainyl)-1-H-tetrazole; 5-(heneicosa-6,9,13,16-tetrainyl)-1-H-tetrazole; 5-(Eicosa-7,
10,13,16-tetrainyl)-1-E-tetrazole; 5-(nonadeca-4,7,10-)lynyl)-1-1
1-tetrazole; 5-(octadeca-7,10,13-)rynyl)-1
-B-tetrazole: 5-(-r-(j?-7(Zl, 13(Zl-diey-4,10-cyinylI-x-11-tetrazole;
5-(Eicosa-7(Z), 10(Zl), 13(Z
l-)-dien-4-ynyl) -1-#-tetrazole and 5-(eicosa-4(Z), T(Z), 13(Z)-trien-10-ynyl 1-1-7/-tetrazole , got .

Preparation of Example 7 Hydroxylamine hydrochloride (0,9s y ) was dissolved in water (
Z 1 tnl ) and methanol (1.65 ml)
Dissolved in 1ON aqueous sodium hydroxide (7-7rnl
)'l]l-packed. The resulting solution was diluted with methanol (
21m/) Medium Eicosa-5 (Z), 8 (Z), 11 (Z
), 14(Z)-methyl tetraenoate (1,22,91
7. After 1 hour, the mixture was adjusted to pH 5 with hydrochloric acid.
The mixture was acidified and then extracted with ether. The extracts were dried, evaporated and the residue was chromatographed on silica gel in methylene chloride/methanol/ammonium hydroxide (40/5/0.3; v/v/V).
The title compound was obtained as an oil; 3 m
r Spectrum 0.85 (triplet, 3E, H-20)?
1.30 (multi-lane, 6E, H-1'l, B-18 and u
-191: about t, 7 (multiml!, 6H, H-3, ll
-4 and B-t6); Zos (triple line, 277.77
-21 Column 2.75 (multiplet, 6E%H-7,1l-1
o, 11-133 and 5.2-5.5 p p m (
Multiplet, 8H1 olefinic hydrogen 1. Negative spectrum m/'g=319 (molecular ion).

Example 8 Production of acyl hydroxylamine derivatives of various unsaturated fatty acids Following the same method as in Example 7, Eicosa-5 (Yume Z),
8(Z), 11(Zl, t4(Zl-methyl tetraenoate instead of the following starting angle: Heneicosa-5(Z),
8(z), 11(Z), 14(Z)-methyl tetraenoate; nonadeca-5(2), s (Zl, tl(Z).

14(Z)-Methyl tetraenoate; docosa-5(Z), 8(Z), 11(Z), 14(Z)
-Methyl tetraenoate; Heneicosa-s (Z), 14 (Z)-diene-5
．． 11-Soinoic acid methyl 5-Inoic acid methyl;
By using 8 (Zl, 14 (Z) triene-11-ynoic acid methyl), (α) heneicosa-5 (Zl, 8 (Z), 11t
"z), 14 (z>-tetraenoylhydroxylamine; (6) nonadeca-s (Z), 8 (Z), ll
(Z), 14(2′)-tetraenoylhydroxylamine; (C) Docosa-5(Z), 8(Z), 11(Z).

14(Z)-tetraenoylhydroxylamine; (d) heneicosa-8(Z), 14(Z)-diene-5,11-soynoylhydroxylamine; (e) heneicosa-8(2'), 11( Z), 14(
Z)-) Dien-5-ynoylhydroxylamine, oil, nmrO, 89 (triple line, 37/.

R-211; 1.30 (multiplet, 811.E-17, H
-18, Il -19, Horn -20); 1.8
(Multiplet, 4H, H-3, H-16) i2.05 (Multiplet, 2B, #-71 ?2.27 (Triplet, 2B%B-
2) H27~3.0 (multiplet, 6H, H-'l, /7-
1o, j/-13] and 5.2-5.5 (multiplet, 6E
, olefinic hydrogen), mass spectrum m/e
= 314 (molecular ion -0B); and ω heneicosa -5 (Z), 8 (Z), 14 (Z) -
1 Lien-11-ynoylhydroxylamine.

Example 9 Heneicosa-5,8,11,14-tetreinoic acid (130 ■) was dissolved in methylene chloride (3-), and thionyl chloride (104 ■) was dissolved in methylene chloride (2,6d).
) A solution of FI and methylformamide (5■) was added. After 3 hours at 25°C the solution was evaporated. This residue was mixed with water (0.4 mg l and methanol (0.4 t) to which sufficient IN aqueous potassium hydroxide was added to bring the pH to 9.
A solution of hydroxylamine hydrochloride (58 µ) and sodium bicarbonate (70 η1) in 100 μl, ) was added.
After minutes, ether (2 n tne ) and 1.0 hydrochloric acid (
1 (Lm/litre) was added. The organic solution was dried, evaporated and the residue was chromatographed on silica gel with methylene hydrochloride/methanol/hydroxide/monium (404
10,3; τ/v/v) to give the title compound as a solid with a melting point of 85-88°C.

In the same manner as in Example 10, according to the method of Example 9, Heneicosa-5,8
,11,14-tetrainoic acid instead of the following starting materials η eicosa-5,B,11',14-tetrainoic acid; nonadeca-5,8,11,14-tetrainoic acid; docosa -5,8,11,14-tetrainoic acid; eicosa-6,9,12,15-tetrainoic acid; dococer-6,9,12,15-tetrainoic acid; eicosa-4,7 ,10,13-tetrainoic acid- docosa-4,7,10,13-tetrainoic acid; docosa-7,10',13,16-tetrainoic acid; heneicosa-7,10,13,16 -tetriinoic acid; nonadeca-8,11,14-1-triinoic acid; and eicosa-5,8,11-triinoic acid; .14-tetrainoylhydroxylamine; (b) Nonadeca-5,8,11,14-tetrainoylhydroxylamine; (C) Dodecyl 5.8.11-14-tetrainoylhydroxylamine, melting point 97-99°C; (ti
) Eicosa-6,9,12,15-tetrainoylhydroxylamine; (1) Toco→1--6.9,12.15-tetrainoylhydroxylamine; (g) Eicosa-4,7,10, 13-tetrainoylhydroxylamine; Cg) docosa-4,7,10,13-tetrainoylhydroxylamine; (A) docosa-7,10,13,16-tetrainoylhydroxylamine; (i) heneicosa- 7,10,13,16-tetrainoylhydroxylamine; (canonadeca-8,11,14-)liinoylhydroxylamine; and (/r,) eicosa-5,8,11-)liinoylhydroxylamine , .

Example 11 Preparation of benzene (50 ml) containing thionyl chloride (0.125 ml) and dimethylformamide (0.05 ml)
l ) to eicosa-5 (Zj, s (Zl, t
t (Z), 14 (Zl-tetraenoic acid (0,5 g)
The solution was evaporated to dryness under vacuum and the residue was dissolved in ether. The solution was cooled to 0° C. [7] and an excess of soazomethane in ether was added.

After 2 hours the solution was evaporated to dryness under vacuum and the residue was dissolved in tetrahydrofuran (10m).

Water (5-) and trifluoroacetic acid (1-) were added to the resulting solution.
11 Reaction mixture f to which 7 m of the mixture was added: left for 4 hours, diluted with water 17 and then extracted with hexane. The extract was dried and evaporated and the residue was chromatographed on silica gel with hexane/ether (3/1;
v/v) to obtain the title chemical food as an oil; n
mr spectrum 0,85 (triplet, 3H, 77-21)
;1.25 (multiplet, 61f, If -18, H-1
9 and H-20); 1.75 (multiplet, 21f, 7N-
t71 iZO(multiplet, 2H,H-41; Zl(multiplet, 2H17/-51:z38(three S#!, 2H,B-
3); about 28 (multiplet, 6H, R-8, H-11H-1
41; 4.20 (single line, 277, H-1); and 5.
3-5.5 ppm (multiphase, 8H, olefinic hydrogen).

Example 12 In the same manner as manufacturing the conductor, according to the method of Example 11, Eicother-5 (21
, 8(Z), 11(Z), 14(Z)-tetraenoic acid in place of the following starting material eicosa-5,8,11,14-tetrainoinoic acid.
・ □ - Mortar 1 Nonadeka - 5 (Z), 8 (Z), 11 (Z) 114 (
Z)-tetraenoic acid; nonadeca-5,8,11,14-tetrainoic acid: octadeca-5(Z), 8(Z), 11(Z).

14(Z)-tetraenoic acid; octadeca-4,7,10,13-tetrainoic acid; heneicosa-4(Z), ? (Z), 1G (Z), 1a
(Zl-tetraenoic acid; heneicosa-4,7,10,13-tetreinoic acid; nonadeca-5,8,11,14-tetreinoic"r
Gide; Heneifu 1ner 5.8,11.14-tetrainoic acid; ; Heneicosa-6,9,12,15-tetrainoic acid.

Eicosa-7,10,13,16-tetrinoic acid; Nonadeca-4,7,10-) rhinoic acid; Octa-7,10,13-) rhinoic acid; Heneicosa-8(2), 14 (Z)-diene-5,
11-Soinoic acid; Heneicosa-8(Z), 11(Z), 14(Z)-triene-5-inoic acid; and Heneicosa-
5 (Z), 8 (Z), 14 (Z)-triene-11
l-hydroxyeicosa-6,9,12°15-tetrain-2-one; l-hydroxyeicosa-6(Z), 9(Z), respectively.

121Zl, ts(Z)-tetraen-2-one:l
-hydroxyeicosa-6,9,12,15-tetrine-2-one; l-hydroxynonadeca-s (Z); 9 (Z)
.

12(Zl, 15(Z)-tetraen-2-one; l-
Hydroxynonadec-5,8,11-14-tetrine-2-one; 1-hydroxydocosa-5(Z), 8(Z).

11(2), 14(Z)-tetraen-2-one; l-
Hydroxydocosa-5,8,11-14-tetrine-
2-one; l-hydroxyeicosa-6,9,12,15-tetrine-2-one; l-hydroxydocosa-6,9,12,15-tetrine-2-one; l-hydroxyeicosa-4 ,7,10,13-tetrine-2-one; l-hydroxydocosa-4,7,], O,l 3-tetrine-2-one; l-hydroxydocosa-7-10,13,16-tetrine- 2-one; l-hydroxyheneicosa-8,11,14°17-
Tetrain-2-one; l-hydroxyeicosa-5,8,11-) IJyn-2-one; 1-hydroxynonadeca-8,11,14-)lyne-
2-one; l-hydroxide"?-9 (Z), 15 (z)
-Diene-6,12-diyn-2-one: 1-hydroxydocosa-9,12,15-trien-6-yn-2
-71; and 1-hydroxydocosa-6 (Z), 9 (Z)
.

15(Z)-1-dien-12-yn-2-one was obtained.

Example 13 5-(Eicosa-4,7,10,
13-tetrainyl) -1-H-tetra-1-l (50
Sodium methoxide (82■) was added to the solution of 0++y). The solution was then evaporated to dryness to obtain the sodium salt of 5-(eiko?-4.7.10-13-tetrainyl 1-1-#-tetrazole.

Similarly, X is 1-7 futetrazol-5-yl or C(
0) Shadow formula of the free acid that is NEOII +11.12J or all compounds of (3) include potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferrous It could be converted into iron, manganic salt, etc. .

Example 14 5-(eicosa-4,7,10,13-tetrainyl)
A two-fold stoichiometric excess of IN hydrochloric acid was added to an aqueous solution of -1-H-tetrazole sodium salt. The solution was then extracted with ether and the extracts were dried and evaporated to give 5-(eicosa-4,?,10.13-tetranyl).
-1-H-tetrazole was obtained.

In Examples 15-22, the active ingredient is heneicosa
It was 5,8,11,14-tetrainoylhydroxylamine. Other compounds of formula +11, (23 or (3)) and pharmaceutically acceptable salts thereof could also be used instead.

Examples Active Ingredients 25 Corn starch 20 Lactose, spray dried 153 Magnesium stearate 2 The above acids were thoroughly mixed and formed into one lined tablet.

Example 16 Active ingredient io.

Lactose, spray dried 148 Magnesium stearate 2 The above acids were mixed and encapsulated in a hard shell gelatin capsule.

Example 17 Active Ingredients 200 Milk sorghum starch 50 Lactose 145 Magnesium stearate 5 The above ingredients were mixed well and formed into one lined tablet. .

Example 18 Ingredients 11 Active Ingredients per Tablet 108 Lactose 15 Corn Starch 25 Magnesium Stearate 2 The above ingredients were mixed and encapsulated in hard shell gelatin capsules.

Example 19 Ingredients Amount per tablet, ηfi
Resistant component 150 Lactose 92 The above components were mixed and sealed in a hard shell capsule.

Example 20 A pH'l buffered injectable preparation was prepared having the following composition: Ingredients Active Ingredient 0.2yK
M, p04 powder (0.4M solution) 2-KO
H(1 #l 'I) Amount up to H'l Water (distilled water, sterile) Amount up to 20- Example 21 An oral suspension was prepared having the following composition.

Ingredients Active ingredient 0.1g Fumaruki
0,5y sodium chloride
'toy methyl nozo lapen
0.1 granulated sugar 25.
5 g Sorbitol (70% solution) 1'L85
．． 9VeegrLmK (Vandcrbiet company 1
1.0.9 Flavoring agent 0.0
Example 22 A topical formulation was prepared having the following composition:
Intermediate active compound
0.2~2Span 6o
2 Tween GO2 mineral oil 5 ov
=pm (petrolatutn) 10 Methylparaben 0.15 Probyl non-lapene 0.05BH
A (Butylated Hydroxylinisole) 0.01 water
Combine all of the above ingredients except water and add enough water to 100 ml while stirring.
Heated to 0°C. Then, a sufficient amount of water was slowly added to the mixture at 60°C with vigorous stirring to emulsify the ingredients.Water was then added in an amount sufficient to bring the temperature to 110°I.

Example 23 Compounds of the invention were tested for their ability to inhibit xygenase as follows: Experimental Procedure 1, Cell Preparation: Cells were tested in healthy donors who had not received any drug for at least 7 days. Heparinized blood 200-300
PMN was prepared from - by the Ficoll-Hypaque gradient method. Generally, pMN has a purity of 98%.
Well, the viability was evaluated as better than 95% by the dye exclusion method. This cell was 1. OmM
It was suspended in phosphate buffered saline containing CaCl, (pH 7.4) and 0.1 opalpmin and used within 30 minutes.

2 Lipoxygenase rating: 5 in total volume 0.2-
The temperature was kept at 37°C for 1 minute. Add 7 rachidonic acid 1-(1''' (lx unless otherwise specified) to a suspension of cells (approximately 5
lo −' M, and approximately 300.000 c p m)
was added to start the reaction. Prior to the addition of the above-mentioned substrate, the test substance was added to the cells at an appropriate concentration, and the cells were heated to 37℃ for 5 minutes.
Preheated for 1 minute. Generally, stock solutions of test substances are prepared in ethanol (or other suitable solvent) and diluted with warm buffer or water.

The final degree of ethanol during incubation was not allowed to exceed 2%. Control material containing no test substance and boiling point 0.6-
The culture was stopped by adding 100 ml of chlorine, vortexed, and kept on ice for 30 min. % (5-HETE methyl ester) and deionized water 1, arachidonic acid and Extraction and purification of the lipoxygenase product was carried out using a Baker's disposable CO extraction column (1 ml, 1 g). The column was prewashed with methanol (2,0d) and then with deionized water (2-). After removing most of the solvent, the supernatant 2.0- was applied to the extraction column and the solvent was allowed to flow through. The column was then washed with 5 flIl of deionized water and the effluent was discarded. The column was then flushed with 2,0 txl of MeOH, the effluent was forced through with N, collected, and the solvent was removed in a vacuum oven overnight. Residual mobile phase (MeOH75: H2O
25:HACO,Ol) was carefully dissolved in 125 μl, and a total of 10 μm aliquots were taken to evaluate the recovery. Some molecules of the extract from the "control" tube
The retention times of the cyclooxygenase and lipoxygenase products were determined by injecting into a C-18 reversed phase column and measuring the OD at 244 nM and by collecting 1 minute fractions and quantifying the radioactive material. Based on the information, auto-inject each of the extracts g = (II' I 5P
) I/CL was injected into the column, fractions (all 6) were collected using a fraction collector according to the program, and both fractions were counted for radioactivity using a Packard liquid scintillation spectrometer. From this data, the percent yield of the different products formed and the percent inhibition of these by the test compounds were calculated.

Result % Inhibition in 10-'Molar Degree Compound of Example No. 5-11ETF LTB
.

11 61 655A
62 857
96 995C7388 99192 10(6) 41a 41a
s(g) 50alb5 oaeb(α)
Percent Inhibition at Total Lipoxygenase Product Inhibition Test (6) 4X10-11 Molar Concentration Example 24 Compounds of the invention were tested for their ability to inhibit platelet aggregation as follows.

EXPERIMENTAL PROCEDURE Human venous blood from healthy, drug-naive blood donors was collected in a 15 ml vacutainer and anticoagulated with 11.4% sodium citrate-Hm/. This blood, 5
Orvatl GLC-2B centrifugation at room temperature for 150. ! / for 15 minutes, and the supernatant platelet-rich plasma (PRP) was collected by suction. Weak plasma of platelets (4p PPPI, no Rp removed,
m by Eppendorf centrifugation at room temperature for 12
800. Centrifuge mushrooms 10-6 to 5X10 for 3 minutes in lit
-'#) or collagen (4s ~ 60 μy/nt,
Vitrogen 1 was introduced into 1 ml of PRP containing 10 μl of test compound or excipient at various concentrations and 500 rpm in a tappet in coagulation form. The mixture was kept at 37° C. for 5 minutes while stirring with Fl.

The increase in light transmission (ΔT) was recorded from each solidification curve. The percent inhibition of the clotting curve by the test compound was calculated using the following formula: Control ΔT Then, for each test compound, a % inhibition vs. concentration curve was drawn on semi-log paper and the me corresponding to 50% inhibition was calculated as the IC of this compound. ,. It is expressed in a closed form.

The test specimens were dissolved in ethanol or DMF.

+11 G, V, R, Born and M, /, Cros
s.

”The Aggregation of'Bl
oodplateats”, /, physiol,
16 B, 178 (1963).

Example 25 Heneicosa-5,8,11,14-tetranoylhydroxylamine was administered subcutaneously to 6 female 5w1ss Tl'abster hinoki-qusu at a dose of 9 in 100y19 and observed for 21 days. None of the 11 animals died. Therefore, the LD of this compound. is thicker than 9 in 100■/.

Patent Applicant: Syntex (nee Niss A) Inc.

Claims (1)

[Claims] 1. Formula [wherein A is C=C or C=C, B is C=C or C=C, and D is c-c, C=C or C;C Derei, E is C-C=,
C=C or C=C and -F is c-c, C=C or C-
C, and Z is CH,, CM, CM, , CM, CH,
CH,, CM, CH, CH, CM, and X are 1
-H-tetrazol-5-yl, C(0)NHOH%(,'(0)CHlOH or CON
H, and pharmaceutically acceptable non-toxic salts thereof. 2. Claim 1 in which the compound is a compound represented by formula (11) and a pharmaceutically acceptable non-toxic salt thereof
Compounds described in Section. & Z is -CH, CH, -CH, C1i, CH, or -○H, CH, C"H, CM, the compound according to claim 2. 4. X is 10 (0 ) NHOH. 5. A, B, D and F are c==c and E is C-C.
2.3 or 4. Compounds described in Section. 6. The compound according to claim #2.3 or 4, wherein A, B, D and F are C═C and E is C-C. 7. Compound 5-(nonadeca-4(Z), ?(Z), 10(Z)13
(Z)-tetraenyl l-1-H-tetrazole; eicosa-5(Z), 8(Z), 11(Z), 14(Z
)-tetraenoylhydroxylamine; l-hydroxy to/Eif-6(Z), 9(Zl, 12(Z), 15
(Z)-tetraen-2-one; docosa-5,8-,1
1,, l'i4-tetrainoylhydroxylamine; heneicosa-8(Z), xttz+, 14(Zl-trien-5-ynoylhydroxylamine; or eicosa-5(Z), 8(Z), 11( Zl, 14 (Z
)-tetraenamide, and a pharmaceutically acceptable non-toxic salt thereof. 8. The claim that the compound is heneicosa-5,8,11,14-tetrainoylhydroxylamine! ! , a compound according to item 2 and a pharmaceutically acceptable non-toxic salt thereof. 9. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable non-toxic salt thereof,
A pharmaceutical composition comprising in admixture with at least one pharmaceutically acceptable excipient. 10. A compound according to any one of claims 1 to 8 for use in preventing or treating inflammation, pain, allergic reactions or platelet coagulation. 11, Formula [wherein A is C=C or C=C, Bd, C=C or C=C, D is c-c%c=c or c=-c, E is c-
c%c=c, or C=C, and F is t'-c, C=C
, or C=C, and Z is 10E, , -CH, CH3,
-CMtCll, CM, , -CM, C1l, CM, C
H3, and X is 1-E-tetrazol-5-yl, C(OINHOH, C<0)CM, OH or CONH,
] A method for producing a compound and a pharmaceutically acceptable non-toxic salt according to claim 1, wherein α) X is C
Formulas (1), (2) and (3) which are 0OH or nitrile
b) converting compounds of formulas (1), (2) and (3) in which X is nitrile to 1-H-tetrazole compounds; c) reaction in which X is C0OH or C0OH Formulas (1), (2) and (
3) is reacted with hydroxylamine to produce an acyl hydroxylamine; or compounds of formulas (11, +23 and (3), where X is NO, are rearranged to produce an acyl hydroxylamine; or Compounds of formulas (1), (2) and (3) in which X is an oxime are brewed to produce cyclosylhydroxylamine; d) X is diazoketone -CtO)CHN! Compounds of formulas (1), (2) and (3) are reacted with an acid to produce a hydroxymethyl ketone: or X is -C0
Converting the compounds of formulas (1), (2) and (3) which are 011 into hydroxymethyl ketone compounds; e) Formula (1)
), (2) or (3) into its salt; or f) converting the salt of the compound of formula (11, (2) or (3) into the free compound). Compounds according to claim 1 and processes for their preparation therein: 1? A compound of formula (1), (2) or (3) as defined in claim y1, except that -X is a nitrile.